While it is known that the sugar attachments of pharmaceutically important natural products often define their corresponding biological activity, until recently, efficient methods to alter these essential carbohydrate appendages, and thereby systematically explore their carbohydrate-based structure-activity relationships (SAR), was lacking. In recent years, we have developed two strategies to rapidly glycosylate natural products - in vitro glycorandomization (a chemoenzymatic process) and, more recently, neoglycorandomization (chemoselective-ligation based process). As Lab Program 2 of the University of Wisconsin National Cooperative Drug Discovery Group (UW NCDDG), this proposal outlines a systematic application of these two unique strategies toward diversification of a wide range of natural product parent scaffolds (including a number from UW NCDDG Program 1, Professor Shen) with previously indicated anticancer activities. Specifically, the proposed studies are designed to assess the general applicability of chemoenzymatic and chemoselective ligation-based glycorandomization to significantly enhance accessible natural product-based diversity and, in conjunction with the unique screening and downstream analysis capabilities of the UW NCDDG, will present perhaps the broadest correlation to date between the biological activity of natural products and the specific contributions invoked by their attached carbohydrates. More importantly, as mandated by the NCDDG, the parent scaffolds were also selected to significantly bias the ultimate outcome toward the identification of promising anticancer leads within the intended funding period and diversity directives will specifically evolve based upon the constant consultation of the novel screening/biological analysis/clinical components of the UW NCDDG